PMID- 31830478
OWN - NLM
STAT- MEDLINE
DCOM- 20200123
LR  - 20200123
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 241
DP  - 2020 Jan 15
TI  - High glucose augments ROS generation regulates mitochondrial dysfunction and 
      apoptosis via stress signalling cascades in keratinocytes.
PG  - 117148
LID - S0024-3205(19)31076-8 [pii]
LID - 10.1016/j.lfs.2019.117148 [doi]
AB  - Mitochondria are fascinating structures of the cellular compartments that 
      generate energy to run the cells. However, inherent disorders of mitochondria due 
      to diabetes can cause major disruption of metabolism that produces huge amount of 
      reactive oxygen species (ROS). Here we study the elevated level of ROS provoked 
      by high glucose (HG) environment triggered mitochondrial dysfunction, 
      inflammatory response and apoptosis via stress signalling pathway in 
      keratinocytes. Our results demonstrated that elevated glucose level in 
      keratinoctes, increase the accumulations of ROS and decrease in cellular 
      antioxidant capacities. Moreover, excess production of ROS was associated with 
      mitochondrial dysfunction, characterized by loss of mitochondrial membrane 
      potential (DeltaPsim), increase in mitochondrial mass, alteration of mitochondrial 
      respiratory complexes, cytochrome c (Cyt c) release, decrease in mitochondrial 
      transcription factor A (TFAM) and increase in mitochondrial DNA (mtDNA) 
      fragmentation. Damaged mtDNA escaped into the cytosol, where it engaged the 
      activation of ERK1/2, PI3K/Akt, tuberin and mTOR via cGAS-STING leading to IRF3 
      activation. Pre-treatment of pharmacological inhibitors, ERK1/2 or PI3K/Akt 
      suppressed the IRF3 activation. Furthermore, our results demonstrated that 
      activation of IRF3 in HG environment coinciding with increased expression of 
      inflammatory mediators. Excess production of ROS interfered with decreased in 
      cell viability, increased lysosomal content and expression of FoxOs, leading to 
      cell cycle deregulation and apoptosis. Pre-treatment of N-acetyl-l-cysteine (NAC) 
      significantly reduced the HG-induced cell cycle deregulation and apoptosis in 
      keratinocytes. In conclusion, increased oxidative stress underlies the decrease 
      in antioxidant capacities and mitochondrial dysfunction in HG environment 
      correlate with inflammation response and apoptosis via ERK1/2-PI3K/Akt-IRF3 
      pathway in keratinoctes.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Rizwan, Huma
AU  - Rizwan H
AD  - School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 
      751024, India.
FAU - Pal, Sweta
AU  - Pal S
AD  - School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 
      751024, India.
FAU - Sabnam, Silpa
AU  - Sabnam S
AD  - School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 
      751024, India.
FAU - Pal, Arttatrana
AU  - Pal A
AD  - School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 
      751024, India; Department of Zoology, School of Life Sciences, Mahatma Gandhi 
      Central University, Motihari, Bihar 845401, India. Electronic address: 
      arttatranapal@mgcub.ac.in.
LA  - eng
PT  - Journal Article
DEP - 20191209
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sweetening Agents)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Glucose/*pharmacology
MH  - Keratinocytes/drug effects/metabolism/*pathology
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mice
MH  - Mice, Hairless
MH  - Mitochondria/drug effects/metabolism/*pathology
MH  - Oxidative Stress/*drug effects
MH  - Reactive Oxygen Species/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Sweetening Agents/pharmacology
OTO - NOTNLM
OT  - Apoptosis
OT  - High glucose
OT  - IRF3
OT  - Inflammation
OT  - cGAS-STING
OT  - mtDNA damage
EDAT- 2019/12/13 06:00
MHDA- 2020/01/24 06:00
CRDT- 2019/12/13 06:00
PHST- 2019/10/02 00:00 [received]
PHST- 2019/12/04 00:00 [revised]
PHST- 2019/12/05 00:00 [accepted]
PHST- 2019/12/13 06:00 [pubmed]
PHST- 2020/01/24 06:00 [medline]
PHST- 2019/12/13 06:00 [entrez]
AID - S0024-3205(19)31076-8 [pii]
AID - 10.1016/j.lfs.2019.117148 [doi]
PST - ppublish
SO  - Life Sci. 2020 Jan 15;241:117148. doi: 10.1016/j.lfs.2019.117148. Epub 2019 Dec 
      9.